Three-dimensional solution structure of conotoxin psi-PIIIE, an acetylcholine gated ion channel antagonist.
The three-dimensional structure of conotoxin psi-PIIIE, a 24-amino acid peptide from Conus purpurascens, has been solved using two-dimensional (2D) 1H NMR spectroscopy. Conotoxin psi-PIIIE contains the same disulfide bonding pattern as the mu-conotoxins, which target skeletal muscle sodium channels, but has been shown to antagonize the acetylcholine gated cation channel through a noncompetitive mechanism. Structural information was obtained by the analysis of a series of 2D NOESY spectra as well as measurement of coupling constants from 1D 1H and PE-COSY NMR experiments. Molecular modeling calculations included the use of the distance geometry (DG) algorithm, simulated annealing techniques, and the restrained molecular dynamics method. The resulting structures are considerably similar to the previously published structures for the mu-conotoxins GIIIA and GIIIB, despite the lack of sequence conservation between conotoxin psi-PIIIE and the mu-conotoxins. The structure consists of a series of tight turns, each turn occurring in the position analogous to those of turns described in mu-GIIIA and mu-GIIIB. This suggests the disulfide bonding pattern is able to largely direct the structure of the peptides, creating a stable structural motif which allows extensive sequence substitution of non-cystine residues.
Mitchell
S S
SS
Department of Medicinal Chemistry, University of Utah, Salt Lake City 84112, USA.
Shon
K J
KJ
Foster
M P
MP
Davis
D R
DR
Olivera
B M
BM
Ireland
C M
CM
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008978:Mollusk Venoms / Q000737:chemistry* / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry* / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D026941:Sodium Channel Blockers; D012996:Solutions; D020960:omega-Conotoxins
D008978:Mollusk Venoms; D018733:Nicotinic Antagonists; D010455:Peptides; D026941:Sodium Channel Blockers; D012996:Solutions; D020960:omega-Conotoxins; C107492:psi-conotoxin PIIIE